The objective of this project is develop intraoral controlled-release therapeutic systems for antibiotics/antimicrobials and antifungal agents for the treatment of periodontal disease, AID-related oral diseases and other opportunistic oral mycotic infections. Biocompatible copolymers of hydroxyethyl methacrylate (HEMA) and methyl methacrylate (MMA) were used to produce a membrane-controlled delivery system for tetracycline that should be suitable for short-term intraoral treatment of periodontal disease. Results with this system have shown that the hydrogel copolymers used in the clinically tested Intraoral Fluoride Releasing Device also can be used for the delivery of large organic molecules in vivo. In a study in monkeys, ten days of treatment with tetracycline controlled-release pellets releasing 0.4 to 1.0 mg of tetracycline per day produced significant decreases in crevicular fluid flow, number of bleeding sites on probing, and bacterial morphotypes associated with periodontal disease in subgingival plaque samples. Prototype controlled-release pellets for chlorhexidine were fabricated using the same copolymers used in the tetracycline and fluoride systems. These pellets released biologically active chlorhexidine for 30 days. It should be possible to use this technology to develop intraoral controlled-release delivery systems for the lower molecular weight antifungal agents. Such systems could be beneficial in immunocompromised patients.